The goal of these studies is to test novel therapeutic strategies both to combat graft rejection and to produce a state of specific host unresponsiveness. The study uses new agents targeted selectively at the interleukin 2 receptor (IL-2R) of activated lymphocytes as an adjunct to sub-therapeutic doses of cyclosporine (CsA) in the treatment of rat recipients of cardiac allografts. The specific aims are: (1) To determine the effectiveness of Il-2R targeted agents plus sub-therapeutic doses of CsA in preventing or treating acute allograft rejection: Mouse anti-rat ART18 and ART 65 MoAbs recognize distinct epitopes of the rat IL-2R molecule. As all antigen activated T cells, certain B cells and macrophages, but not resting or memory cells, express Il-2R,IL-2R directed therapy should create a selective immune defect in the transplant recipient. Peri-transplant treatment with MoAbs of different isotypes and epitope specificity plus low dose CsA will be initiated on the day of grafting, followed by a trail to define their optimal dose and duration. Delayed therapy will be introduced at defined periods after transplant in an attempt to reverse rejection episode(s). This novel immunosuppressive regimen has been proved highly effective in pilot experiments. (2) To test the efficacy of IL-2R targeted therapy plus sub- therapeutic doses of CsA in combating accelerated graft rejection. The survival of cardiac allografts and the kinetics of IL-2R expression will be monitored in rats presensitized with skin grafts or challenged with dendritic cells. Pre-, peri-, or post- operative therapy with anti-IL-2R MoAbs plus low dose CsA will be used to depress sensitization and to modulate accelerated (48hr) rejection. In preliminary studies, combination therapy abrogates accelerated rejection and converts primarily humoral graft injury into later cellular rejection. (3) To define the mechanisms of specific unresponsiveness produced by the these combination therapies: Recent data suggest that anti- IL-2R MoAb and CsA produce host unresponsiveness by abrogating alloagressiveness of IL-2R+ cells and sparing cell subpopulations with suppressor characteristics. Treatments will be monitored as to their effects on IL-2R+ recipient cells using FACS, immunohistological evaluation and immunoradiometric assay for detection of soluble IL-2R. The immunological status of graft recipients will be assessed in vitro. In vivo, adoptive transfers of individual cell subsets from allograft recipients to untreated rate given test grafts, or to T cell deprived B hosts will evaluate their differential effector or suppressive properties.